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An efficient allocation of limited resources in low-income settings offers the opportunity to improve population-health outcomes given the available health system capacity. Efforts to achieve this are often framed through the lens of "health benefits packages" (HBPs), which seek to establish which services the public healthcare system should include in its provision. Analytic approaches widely used to weigh evidence in support of different interventions and inform the broader HBP deliberative process however have limitations. In this work, we propose the individual-based Thanzi La Onse (TLO) model as a uniquely-tailored tool to assist in the evaluation of Malawi-specific HBPs while addressing these limitations. By mechanistically modelling-and calibrating to extensive, country-specific data-the incidence of disease, health-seeking behaviour, and the capacity of the healthcare system to meet the demand for care under realistic constraints on human resources for health available, we were able to simulate the health gains achievable under a number of plausible HBP strategies for the country. We found that the HBP emerging from a linear constrained optimisation analysis (LCOA) achieved the largest health gain-∼8% reduction in disability adjusted life years (DALYs) between 2023 and 2042 compared to the benchmark scenario-by concentrating resources on high-impact treatments. This HBP however incurred a relative excess in DALYs in the first few years of its implementation. Other feasible approaches to prioritisation were assessed, including service prioritisation based on patient characteristics, rather than service type. Unlike the LCOA-based HBP, this approach achieved consistent health gains relative to the benchmark scenario on a year- to-year basis, and a 5% reduction in DALYs over the whole period, which suggests an approach based upon patient characteristics might prove beneficial in the future.

IntroductionMathematical modelling is a commonly utilised tool to predict the impact of policy on health outcomes globally. Given the persistently high levels of maternal and perinatal morbidity and mortality in sub-Saharan Africa, mathematical modelling is a potentially valuable tool to guide strategic planning for health and improve outcomes.MethodsThe aim of this scoping review was to explore the characteristics of mathematical models and modelling studies evaluating the impact of maternal and/or perinatal healthcare interventions or services on health-related outcomes in the region. A search across three databases was conducted on 2nd November 2023 which returned 8660 potentially relevant studies, from which 60 were included in the final review. Characteristics of these studies, the interventions which were evaluated, the models utilised, and the analyses conducted were extracted and summarised.ResultsFindings suggest that the popularity of modelling within this field is increasing over time with most studies published after 2015 and that population-based, deterministic, linear models were most frequently utilised, with the Lives Saved Tool being applied in over half of the reviewed studies (n = 34, 57%). Much less frequently (n = 6) models utilising system-thinking approaches, such as individual-based modelling or systems dynamics modelling, were developed and applied. Models were most applied to estimate the impact of interventions or services on maternal mortality (n = 34, 57%) or neonatal mortality outcomes (n = 39, 65%) with maternal morbidity (n = 4, 7%) and neonatal morbidity (n = 6, 10%) outcomes and stillbirth reported on much less often (n = 14, 23%).DiscussionGoing forward, given that healthcare delivery systems have long been identified as complex adaptive systems, modellers may consider the advantages of applying systems-thinking approaches to evaluate the impact of maternal and perinatal health policy. Such approaches allow for a more realistic and explicit representation of the systems- and individual- level factors which impact the effectiveness of interventions delivered within health systems.

IntroductionThe COVID-19 pandemic and the restriction policies implemented by the Government of Malawi may have disrupted routine health service utilisation. We aimed to find evidence for such disruptions and quantify any changes by service type and level of health care.MethodsWe extracted nationwide routine health service usage data for 2015-2021 from the electronic health information management systems in Malawi. Two datasets were prepared: unadjusted and adjusted; for the latter, unreported monthly data entries for a facility were filled in through systematic rules based on reported mean values of that facility or facility type and considering both reporting rates and comparability with published data. Using statistical descriptive methods, we first described the patterns of service utilisation in pre-pandemic years (2015-2019). We then tested for evidence of departures from this routine pattern, i.e., service volume delivered being below recent average by more than two standard deviations was viewed as a substantial reduction, and calculated the cumulative net differences of service volume during the pandemic period (2020-2021), in aggregate and within each specific facility.ResultsEvidence of disruptions were found: from April 2020 to December 2021, services delivered of several types were reduced across primary and secondary levels of care-including inpatient care (-20.03% less total interactions in that period compared to the recent average), immunisation (-17.61%), malnutrition treatment (-34.5%), accidents and emergency services (-16.03%), HIV (human immunodeficiency viruses) tests (-27.34%), antiretroviral therapy (ART) initiations for adults (-33.52%), and ART treatment for paediatrics (-41.32%). Reductions of service volume were greatest in the first wave of the pandemic during April-August 2020, and whereas some service types rebounded quickly (e.g., outpatient visits from -17.7% to +3.23%), many others persisted at lower level through 2021 (e.g., under-five malnutrition treatment from -15.24% to -42.23%). The total reduced service volume between April 2020 and December 2021 was 8 066 956 (-10.23%), equating to 444 units per 1000 persons.ConclusionWe have found substantial evidence for reductions in health service delivered in Malawi during the COVID-19 pandemic which may have potential health consequences, the effect of which should inform how decisions are taken in the future to maximise the resilience of healthcare system during similar events.

BackgroundUNAIDS has established new program targets for 2025 to achieve the goal of eliminating AIDS as a public health threat by 2030. This study reports on efforts to use mathematical models to estimate the impact of achieving those targets.Methods and findingsWe simulated the impact of achieving the targets at country level using the Goals model, a mathematical simulation model of HIV epidemic dynamics that includes the impact of prevention and treatment interventions. For 77 high-burden countries, we fit the model to surveillance and survey data for 1970 to 2020 and then projected the impact of achieving the targets for the period 2019 to 2030. Results from these 77 countries were extrapolated to produce estimates for 96 others. Goals model results were checked by comparing against projections done with the Optima HIV model and the AIDS Epidemic Model (AEM) for selected countries. We included estimates of the impact of societal enablers (access to justice and law reform, stigma and discrimination elimination, and gender equality) and the impact of Coronavirus Disease 2019 (COVID-19). Results show that achieving the 2025 targets would reduce new annual infections by 83% (71% to 86% across regions) and AIDS-related deaths by 78% (67% to 81% across regions) by 2025 compared to 2010. Lack of progress on societal enablers could endanger these achievements and result in as many as 2.6 million (44%) cumulative additional new HIV infections and 440,000 (54%) more AIDS-related deaths between 2020 and 2030 compared to full achievement of all targets. COVID-19-related disruptions could increase new HIV infections and AIDS-related deaths by 10% in the next 2 years, but targets could still be achieved by 2025. Study limitations include the reliance on self-reports for most data on behaviors, the use of intervention effect sizes from published studies that may overstate intervention impacts outside of controlled study settings, and the use of proxy countries to estimate the impact in countries with fewer than 4,000 annual HIV infections.ConclusionsThe new targets for 2025 build on the progress made since 2010 and represent ambitious short-term goals. Achieving these targets would bring us close to the goals of reducing new HIV infections and AIDS-related deaths by 90% between 2010 and 2030. By 2025, global new infections and AIDS deaths would drop to 4.4 and 3.9 per 100,000 population, and the number of people living with HIV (PLHIV) would be declining. There would be 32 million people on treatment, and they would need continuing support for their lifetime. Incidence for the total global population would be below 0.15% everywhere. The number of PLHIV would start declining by 2023.

BackgroundProspective cohort studies of incident HIV and associated factors among gay, bisexual, and other men who have sex with men (GBMSM) in the United Kingdom are lacking. We report time trends in and factors associated with HIV incidence between 2013 and 2019 among a cohort of GBMSM: the AURAH2 prospective study.Methods and findingsParticipants were recruited through 1 of 3 sexual health clinics in London and Brighton (July 2013 to April 2016) and self-completed a baseline paper questionnaire and subsequent 4-monthly and annual online questionnaires (March 2015 to March 2018), including information on sociodemographics, lifestyle, health and well-being, HIV status, sexual/HIV-related behaviours, and preexposure prophylaxis and postexposure prophylaxis (PrEP/PEP). Incident HIV was ascertained by linkage with national HIV surveillance data from Public Health England (PHE). We investigated the associations of HIV incidence with (1) baseline factors using mixed-effects Weibull proportional hazard models, unadjusted and adjusted for age, country of birth and ethnicity, sexuality, and education level; and (2) time-updated factors, using mixed-effects Poisson regression models. In total, 1,162 men (mean age 34 years, 82% white, 94% gay, 74% university-educated) were enrolled in the study. Thirty-three HIV seroconversions occurred over 4,618.9 person-years (PY) of follow-up: an overall HIV incidence rate (IR) of 0.71 (95% confidence interval (CI) 0.51 to 1.00) per 100 PY. Incidence declined from 1.47 (95% CI 0.48 to 4.57) per 100 PY in 2013/2014 to 0.25 (95% CI 0.08 to 0.78) per 100 PY in 2018/2019; average annual decline was 0.85-fold (p < 0.001). Baseline factors associated with HIV acquisition included the following: injection drug use (6/38 men who reported injection drug-acquired HIV; unadjusted conditional hazard ratio (HR) 27.96, 95% CI 6.99 to 111.85, p < 0.001), noninjection chemsex-related drug use (13/321; HR 6.45, 95% CI 1.84 to 22.64, p < 0.001), condomless anal sex (CLS) (26/741; HR 3.75, 95% CI 1.31 to 10·74, p = 0.014); higher number of CLS partners (HRs >10 partners [7/57]; 5 to 10 partners [5/60]; and 2 to 4 partners [11/293]: 14.04, 95% CI 4.11 to 47.98; 9.60, 95% CI 2.58 to 35.76; and 4.05, 95% CI 1.29 to 12.72, respectively, p < 0.001); CLS with HIV-positive partners (14/147; HR 6.45, 95% CI 3.15 to 13.22, p < 0.001), versatile CLS role (21/362; HR 6.35, 95% CI 2.18 to 18.51, p < 0.001), group sex (64/500; HR 8.81, 95% CI 3.07 to 25.24, p < 0.001), sex for drugs/money (4/55, HR 3.27, 95% CI 1.14 to 9.38, p = 0.027) (all in previous 3 months); previous 12-month report of a bacterial sexually transmitted infection (STI) diagnoses (21/440; HR 3.95, 95% CI 1.81 to 8.63, p < 0.001), and more than 10 new sexual partners (21/471, HRs 11 to 49, 50 to 99, and >100 new partners: 3.17, 95% CI 1.39 to 7.26; 4.40, 95% CI 1.35 to 14.29; and 4.84, 95% CI 1.05 to 22.4, respectively, p < 0.001). Results were broadly consistent for time-updated analysis (n = 622 men). The study's main limitation is that men may not be representative of the broader GBMSM population in England.ConclusionsWe observed a substantial decline in HIV incidence from 2013 to 2019 among GBMSM attending sexual health clinics. Injection drug use, chemsex use, and measures of high-risk sexual behaviour were strongly associated with incident HIV. Progress towards zero new infections could be achieved if combination HIV prevention including Test and Treat strategies and routine commissioning of a PrEP programme continues across the UK and reaches all at-risk populations.

IntroductionThe COVID-19 pandemic has caused widespread disruptions including to health services. In the early response to the pandemic many countries restricted population movements and some health services were suspended or limited. In late 2020 and early 2021 some countries re-imposed restrictions. Health authorities need to balance the potential harms of additional SARS-CoV-2 transmission due to contacts associated with health services against the benefits of those services, including fewer new HIV infections and deaths. This paper examines these trade-offs for select HIV services.MethodsWe used four HIV simulation models (Goals, HIV Synthesis, Optima HIV and EMOD) to estimate the benefits of continuing HIV services in terms of fewer new HIV infections and deaths. We used three COVID-19 transmission models (Covasim, Cooper/Smith and a simple contact model) to estimate the additional deaths due to SARS-CoV-2 transmission among health workers and clients. We examined four HIV services: voluntary medical male circumcision, HIV diagnostic testing, viral load testing and programs to prevent mother-to-child transmission. We compared COVID-19 deaths in 2020 and 2021 with HIV deaths occurring now and over the next 50 years discounted to present value. The models were applied to countries with a range of HIV and COVID-19 epidemics.ResultsMaintaining these HIV services could lead to additional COVID-19 deaths of 0.002 to 0.15 per 10,000 clients. HIV-related deaths averted are estimated to be much larger, 19-146 discounted deaths per 10,000 clients.DiscussionWhile there is some additional short-term risk of SARS-CoV-2 transmission associated with providing HIV services, the risk of additional COVID-19 deaths is at least 100 times less than the HIV deaths averted by those services. Ministries of Health need to take into account many factors in deciding when and how to offer essential health services during the COVID-19 pandemic. This work shows that the benefits of continuing key HIV services are far larger than the risks of additional SARS-CoV-2 transmission.

BackgroundIn the UK, approximately 4,200 men who have sex with men (MSM) are living with HIV but remain undiagnosed. Maximising the number of high-risk people testing for HIV is key to ensuring prompt treatment and preventing onward infection. This study assessed how different HIV test characteristics affect the choice of testing option, including remote testing (HIV self-testing or HIV self-sampling), in the UK, a country with universal access to healthcare.Methods and findingsBetween 3 April and 11 May 2017, a cross-sectional online-questionnaire-based discrete choice experiment (DCE) was conducted in which respondents who expressed an interest in online material used by MSM were asked to imagine that they were at risk of HIV infection and to choose between different hypothetical HIV testing options, including the option not to test. A variety of different testing options with different defining characteristics were described so that the independent preference for each characteristic could be valued. The characteristics included where each test is taken, the sampling method, how the test is obtained, whether infections other than HIV are tested for, test accuracy, the cost of the test, the infection window period, and how long it takes to receive the test result. Participants were recruited and completed the instrument online, in order to include those not currently engaged with healthcare services. The main analysis was conducted using a latent class model (LCM), with results displayed as odds ratios (ORs) and probabilities. The ORs indicate the strength of preference for one characteristic relative to another (base) characteristic. In total, 620 respondents answered the DCE questions. Most respondents reported that they were white (93%) and were either gay or bisexual (99%). The LCM showed that there were 2 classes within the respondent sample that appeared to have different preferences for the testing options. The first group, which was likely to contain 86% of respondents, had a strong preference for face-to-face tests by healthcare professionals (HCPs) compared to remote testing (OR 6.4; 95% CI 5.6, 7.4) and viewed not testing as less preferable than remote testing (OR 0.10; 95% CI 0.09, 0.11). In the second group, which was likely to include 14% of participants, not testing was viewed as less desirable than remote testing (OR 0.56; 95% CI 0.53, 0.59) as were tests by HCPs compared to remote testing (OR 0.23; 95% CI 0.15, 0.36). In both classes, free remote tests instead of each test costing £30 was the test characteristic with the largest impact on the choice of testing option. Participants in the second group were more likely to have never previously tested and to be non-white than participants in the first group. The main study limitations were that the sample was recruited solely via social media, the study advert was viewed only by people expressing an interest in online material used by MSM, and the choices in the experiment were hypothetical rather than observed in the real world.ConclusionsOur results suggest that preferences in the context we examined are broadly dichotomous. One group, containing the majority of MSM, appears comfortable testing for HIV but prefers face-to-face testing by HCPs rather than remote testing. The other group is much smaller, but contains MSM who are more likely to be at high infection risk. For these people, the availability of remote testing has the potential to significantly increase net testing rates, particularly if provided for free.

BackgroundInterventions based around objective measurement of adherence to antiretroviral drugs for HIV have potential to improve adherence and to enable differentiation of care such that clinical visits are reduced in those with high adherence. It would be useful to understand the approximate upper limit of cost that could be considered for such interventions of a given effectiveness in order to be cost effective. Such information can guide whether to implement an intervention in the light of a trial showing a certain effectiveness and cost.MethodsAn individual-based model, calibrated to Zimbabwe, which incorporates effects of adherence and resistance to antiretroviral therapy, was used to model the potential impact of adherence monitoring-based interventions on viral suppression, death rates, disability adjusted life years and costs. Potential component effects of the intervention were: enhanced average adherence when on ART, reduced risk of ART discontinuation, and reduced risk of resistance acquisition. We considered a situation in which viral load monitoring is not available and one in which it is. In the former case, it was assumed that care would be differentiated based on the adherence level, with fewer clinic visits in those demonstrated to have high adherence. In the latter case, care was assumed to be primarily differentiated according to viral load level. The maximum intervention cost required to be cost effective was calculated based on a cost effectiveness threshold of $500 per DALY averted.FindingsIn the absence of viral load monitoring, an adherence monitoring-based intervention which results in a durable 6% increase in the proportion of ART experienced people with viral load < 1000 cps/mL was cost effective if it cost up to $50 per person-year on ART, mainly driven by the cost savings of differentiation of care. In the presence of viral load monitoring availability, an intervention with a similar effect on viral load suppression was cost-effective when costing $23-$32 per year, depending on whether the adherence intervention is used to reduce the level of need for viral load measurement.ConclusionThe cost thresholds identified suggest that there is clear scope for adherence monitoring-based interventions to provide net population health gain, with potential cost-effective use in situations where viral load monitoring is or is not available. Our results guide the implementation of future adherence monitoring interventions found in randomized trials to have health benefit.

ObjectiveEstimates of healthcare costs associated with HIV infection would provide valuable insight for evaluating the cost-effectiveness of possible prevention interventions. We evaluate the additional lifetime healthcare cost incurred due to living with HIV.MethodsWe used a stochastic computer simulation model to project the distribution of lifetime outcomes and costs of men-who-have-sex-with-men (MSM) infected with HIV in 2013 aged 30, over 10,000 simulations. We assumed a resource-rich setting with no loss to follow-up, and that standards and costs of healthcare management remain as now.ResultsBased on a median (interquartile range) life expectancy of 71.5 (45.0-81.5) years for MSM in such a setting, the estimated mean lifetime cost of treating one person was £ 360,800 ($567,000 or € 480,000). With 3.5% discounting, it was £ 185,200 ($291,000 or € 246,000). The largest proportion (68%) of these costs was attributed to antiretroviral drugs. If patented drugs are replaced by generic versions (at 20% cost of patented prices), estimated mean lifetime costs reduced to £ 179,000 ($ 281,000 or € 238,000) and £ 101,200 ($ 158,900 or € 134,600) discounted.ConclusionsIf 3,000 MSM had been infected in 2013, then future lifetime costs relating to HIV care is likely to be in excess of £ 1 billion. It is imperative for investment into prevention programmes to be continued or scaled-up in settings with good access to HIV care services. Costs would be reduced considerably with use of generic antiretroviral drugs.

It is important to have methods available to estimate the number of people who have undiagnosed HIV and are in need of antiretroviral therapy (ART).The method uses the concept that a predictable level of occurrence of AIDS or other HIV-related clinical symptoms which lead to presentation for care, and hence diagnosis of HIV, arises in undiagnosed people with a given CD4 count. The method requires surveillance data on numbers of new HIV diagnoses with HIV-related symptoms, and the CD4 count at diagnosis. The CD4 count-specific rate at which HIV-related symptoms develop are estimated from cohort data. 95% confidence intervals can be constructed using a simple simulation method.For example, if there were 13 HIV diagnoses with HIV-related symptoms made in one year with CD4 count at diagnosis between 150-199 cells/mm3, then since the CD4 count-specific rate of HIV-related symptoms is estimated as 0.216 per person-year, the estimated number of person years lived in people with undiagnosed HIV with CD4 count 150-199 cells/mm3 is 13/0.216 = 60 (95% confidence interval: 29-100), which is considered an estimate of the number of people living with undiagnosed HIV in this CD4 count stratum.The method is straightforward to implement within a short period once a surveillance system of all new HIV diagnoses, collecting data on HIV-related symptoms at diagnosis, is in place and is most suitable for estimating the number of undiagnosed people with CD4 count

It is important for public health and within the HIV vaccine development field to understand the potential population level impact of an HIV vaccine of partial efficacy--both in preventing infection and in reducing viral load in vaccinated individuals who become infected--in the context of a realistic future implementation scenario in resource limited settings.An individual level model of HIV transmission, progression and the effect of antiretroviral therapy was used to predict the outcome to 2060 of introduction in 2025 of a partially effective vaccine with various combinations of efficacy characteristics, in the context of continued ART roll-out in southern Africa.In the context of our base case epidemic (in 2015 HIV prevalence 28% and incidence 1.7 per 100 person years), a vaccine with only 30% preventative efficacy could make a substantial difference in the rate with which HIV incidence declines; the impact on incidence in relative terms is projected to increase over time, with a projected 67% lower HIV incidence in 2060 compared with no vaccine introduction. The projected mean decline in the general adult population death rate 2040-2060 is 11%. A vaccine with no prevention efficacy but which reduces viral load by 1 log is predicted to result in a modest (14%) reduction in HIV incidence and an 8% reduction in death rate in the general adult population (mean 2040-2060). These effects were broadly similar in multivariable uncertainty analysis.Introduction of a partially effective preventive HIV vaccine would make a substantial long-term impact on HIV epidemics in southern Africa, in addition to the effects of ART. Development of an HIV vaccine, even of relatively low apparent efficacy at the individual level, remains a critical global public health goal.

Higher plasma D-dimer levels are strong predictors of mortality in HIV+ individuals. The factors associated with D-dimer levels during HIV infection, however, remain poorly understood.In this cross-sectional study, participants in three randomized controlled trials with measured D-dimer levels were included (N = 9,848). Factors associated with D-dimer were identified by linear regression. Covariates investigated were: age, gender, race, body mass index, nadir and baseline CD4+ count, plasma HIV RNA levels, markers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6]), antiretroviral therapy (ART) use, ART regimens, co-morbidities (hepatitis B/C, diabetes mellitus, prior cardiovascular disease), smoking, renal function (estimated glomerular filtration rate [eGFR] and cystatin C) and cholesterol.Women from all age groups had higher D-dimer levels than men, though a steeper increase of D-dimer with age occurred in men. Hepatitis B/C co-infection was the only co-morbidity associated with higher D-dimer levels. In this subgroup, the degree of hepatic fibrosis, as demonstrated by higher hyaluronic acid levels, but not viral load of hepatitis viruses, was positively correlated with D-dimer. Other factors independently associated with higher D-dimer levels were black race, higher plasma HIV RNA levels, being off ART at baseline, and increased levels of CRP, IL-6 and cystatin C. In contrast, higher baseline CD4+ counts and higher high-density lipoprotein cholesterol were negatively correlated with D-dimer levels.D-dimer levels increase with age in HIV+ men, but are already elevated in women at an early age due to reasons other than a higher burden of concomitant diseases. In hepatitis B/C co-infected individuals, hepatic fibrosis, but not hepatitis viral load, was associated with higher D-dimer levels.

BackgroundThere is interest in expanding ART to prevent HIV transmission, but in the group with the highest levels of ART use, men-who-have-sex-with-men (MSM), numbers of new infections diagnosed each year have not decreased as ARTcoverage has increased for reasons which remain unclear.MethodsWe analysed data on the HIV-epidemic in MSM in the UK from a range of sources using an individual-based simulation model. Model runs using parameter sets found to result in good model fit were used to infer changes in HIV-incidence and risk behaviour.ResultsHIV-incidence has increased (estimated mean incidence 0.30/100 person-years 1990-1997, 0.45/100 py 1998-2010), associated with a modest (26%) rise in condomless sex. We also explored counter-factual scenarios: had ART not been introduced, but the rise in condomless sex had still occurred, then incidence 2006-2010 was 68% higher; a policy of ART initiation in all diagnosed with HIV from 2001 resulted in 32% lower incidence; had levels of HIV testing been higher (68% tested/year instead of 25%) incidence was 25% lower; a combination of higher testing and ART at diagnosis resulted in 62% lower incidence; cessation of all condom use in 2000 resulted in a 424% increase in incidence. In 2010, we estimate that undiagnosed men, the majority in primary infection, accounted for 82% of new infections.ConclusionA rise in HIV-incidence has occurred in MSM in the UK despite an only modest increase in levels of condomless sex and high coverage of ART. ART has almost certainly exerted a limiting effect on incidence. Much higher rates of HIV testing combined with initiation of ART at diagnosis would be likely to lead to substantial reductions in HIV incidence. Increased condom use should be promoted to avoid the erosion of the benefits of ART and to prevent other serious sexually transmitted infections.

Life expectancy for people diagnosed with HIV has improved dramatically however the number of new infections in the UK remains high. Understanding patterns of sexual behaviour among people living with diagnosed HIV, and the factors associated with having condom-less sex, is important for informing HIV prevention strategies and clinical care. In addition, in view of the current interest in a policy of early antiretroviral treatment (ART) for all people diagnosed with HIV in the UK, it is of particular importance to assess whether ART use is associated with increased levels of condom-less sex. In this context the ASTRA study was designed to investigate current sexual activity, and attitudes to HIV transmission risk, in a large unselected sample of HIV-infected patients under care in the UK. The study also gathered background information on demographic, socio-economic, lifestyle and disease-related characteristics, and physical and psychological symptoms, in order to identify other key factors impacting on HIV patients and the behaviours which underpin transmission. In this paper we describe the study rationale, design, methods, response rate and the demographic characteristics of the participants. People diagnosed with HIV infection attending 8 UK HIV out-patient clinics in 2011-2012 were invited to participate in the study. Those who agreed to participate completed a confidential, self-administered pen-and-paper questionnaire, and their latest CD4 count and viral load test results were recorded. During the study period, 5112 eligible patients were invited to take part in the study and 3258 completed questionnaires were obtained, representing a response rate of 64% of eligible patients. The study includes 2248 men who have sex with men (MSM), 373 heterosexual men and 637 women. Future results from ASTRA will be a key resource for understanding HIV transmission within the UK, targeting prevention efforts, and informing clinical care of individuals living with HIV.

Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART.Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results.Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact.

BACKGROUND: The most recent World Health Organization (WHO) antiretroviral treatment guidelines recommend the inclusion of zidovudine (ZDV) or tenofovir (TDF) in first-line therapy. We conducted a cost-effectiveness analysis with emphasis on emerging patterns of drug resistance upon treatment failure and their impact on second-line therapy. METHODS: We used a stochastic simulation of a generalized HIV-1 epidemic in sub-Saharan Africa to compare two strategies for first-line combination antiretroviral treatment including lamivudine, nevirapine and either ZDV or TDF. Model input parameters were derived from literature and, for the simulation of resistance pathways, estimated from drug resistance data obtained after first-line treatment failure in settings without virological monitoring. Treatment failure and cost effectiveness were determined based on WHO definitions. Two scenarios with optimistic (no emergence; base) and pessimistic (extensive emergence) assumptions regarding occurrence of multidrug resistance patterns were tested. RESULTS: In the base scenario, cumulative proportions of treatment failure according to WHO criteria were higher among first-line ZDV users (median after six years 36% [95% simulation interval 32%; 39%]) compared with first-line TDF users (31% [29%; 33%]). Consequently, a higher proportion initiated second-line therapy (including lamivudine, boosted protease inhibitors and either ZDV or TDF) in the first-line ZDV user group 34% [31%; 37%] relative to first-line TDF users (30% [27%; 32%]). At the time of second-line initiation, a higher proportion (16%) of first-line ZDV users harboured TDF-resistant HIV compared with ZDV-resistant viruses among first-line TDF users (0% and 6% in base and pessimistic scenarios, respectively). In the base scenario, the incremental cost effectiveness ratio with respect to quality adjusted life years (QALY) was US$83 when TDF instead of ZDV was used in first-line therapy (pessimistic scenario: US$ 315), which was below the WHO threshold for high cost effectiveness (US$ 2154). CONCLUSIONS: Using TDF instead of ZDV in first-line treatment in resource-limited settings is very cost-effective and likely to better preserve future treatment options in absence of virological monitoring.

The question of whether a score for a specific antiretroviral (e.g. lopinavir/r in this analysis) that improves prediction of viral load response given by existing expert-based interpretation systems (IS) could be derived from analyzing the correlation between genotypic data and virological response using statistical methods remains largely unanswered.We used the data of the patients from the UK Collaborative HIV Cohort (UK CHIC) Study for whom genotypic data were stored in the UK HIV Drug Resistance Database (UK HDRD) to construct a training/validation dataset of treatment change episodes (TCE). We used the average square error (ASE) on a 10-fold cross-validation and on a test dataset (the EuroSIDA TCE database) to compare the performance of a newly derived lopinavir/r score with that of the 3 most widely used expert-based interpretation rules (ANRS, HIVDB and Rega). Our analysis identified mutations V82A, I54V, K20I and I62V, which were associated with reduced viral response and mutations I15V and V91S which determined lopinavir/r hypersensitivity. All models performed equally well (ASE on test ranging between 1.1 and 1.3, p = 0.34).We fully explored the potential of linear regression to construct a simple predictive model for lopinavir/r-based TCE. Although, the performance of our proposed score was similar to that of already existing IS, previously unrecognized lopinavir/r-associated mutations were identified. The analysis illustrates an approach of validation of expert-based IS that could be used in the future for other antiretrovirals and in other settings outside HIV research.